In neurodegenerative diseases such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and cortical basal degeneration (CBD), aggregated forms of the microtubule-associated protein (MAP), tau, are deposited within cells. In AD, the cells involved are predominantly neurons. However, in PSP, CBD and certain frontotemporal dementias (FTDs) filamentous tan deposits are predominantly found in astrocytes and oligodendrocytes. This project focuses on the role of abnormal tau in astrocytes and poses the question, "Does abnormal phosphorylation and/or tan aggregation fuel the inflammatory response by disrupting astrocytic cytoskeletal integrity in vitro and in neurodegenerative disease?" We will compare the state oftau in tissue from PSP, CBD, and FTD cases with that in cultured astrocytes from tau null mice infected with mutant and wild type human tau. Our goal is to determine the role of a specific tau mutation (P301L) on glial cell activation, tan phosphorylation, tau-cytoskeletal association, tau aggregation, and inflammation. We hypothesize that tau dysfunction induced by FTD mutations causes abnormal phosphorylation, destabilization and or rearrangement of the microtubules, inducing cytoskeletal alterations in astrocytes. This internal alteration of the cytoskeleton, perhaps driven by tau phosphorylation, fuels the inflammatory response causing an overproduction of hallmark cytokines and enzymes such as IL-1beta, S100beta, and inducible nitric oxide synthase (iNOS). We will test our hypothesis as follows: 1. We will determine whether markers oftau pathology and inflammation co-segregate with cytoskeletal markers of reactive gliosis using human tissue obtained from cases of PSP, CBD, and selected familial FTD cases. 2. We will determine and assess the impact of specific diseaserelated tau phosphorylation events (identified in Aim 1) on mutant- and wild type-tau-transfected astrocytes and determine whether these events cause increased or decreased chemokine/cytokine production consistent with that observed in Aim 1, above.